Project acronym ALTER-brain
Project Metastasis-associated altered molecular patterns in the brain
Researcher (PI) Manuel VALIENTE
Host Institution (HI) FUNDACION CENTRO NACIONAL DE INVESTIGACIONES ONCOLOGICAS CARLOS III
Call Details Consolidator Grant (CoG), LS4, ERC-2019-COG
Summary Organ colonization is the most inefficient step of metastasis. However, once a few cancer cells manage to re-initiate their growth in the brain, the initial naïve microenvironment, which was not favouring and even actively limiting the number of potential metastasis initiating cells, is slowly rewired into a different ecosystem with pro-metastatic properties. In this project (ALTER-brain), we will study the biology of microenvironment reprogramming to explore innovative ways of treating metastasis.
Microenvironment reprogramming relies on altered molecular patterns that emerge in specific brain cell types simultaneously to the outgrowth of metastases. Dissecting the biology of these emerging patterns and their functional consequences could provide the basis to prevent metastasis but also to treat advances lesions. A key objective of ALTER-brain is the identification of newly established functional networks among previously non-connected components of the microenvironment that are critical to nurture tumour growth.
This research proposal focuses on metastasis in the brain given its rising incidence, poor therapeutic options and short survival rates upon diagnosis. ALTER-brain will use novel (i.e. spontaneous metastasis) and clinically relevant (i.e. relapse after therapy) experimental mouse models of brain metastasis combined with genetically engineered mice in which we will target specific components of the microenvironment. In addition, we will apply novel lineage tracing technologies to understand the origin and emerging heterogeneity of the reprogrammed microenvironment. Given the clinical relevance of our research, human brain metastasis provided by our clinical network will be used to validate key findings.
ALTER-brain will identify key principles underlying the unknown biology of the brain under a specific pathological pressure that might be translated to other highly prevalent disorders affecting this organ in the future.
Summary
Organ colonization is the most inefficient step of metastasis. However, once a few cancer cells manage to re-initiate their growth in the brain, the initial naïve microenvironment, which was not favouring and even actively limiting the number of potential metastasis initiating cells, is slowly rewired into a different ecosystem with pro-metastatic properties. In this project (ALTER-brain), we will study the biology of microenvironment reprogramming to explore innovative ways of treating metastasis.
Microenvironment reprogramming relies on altered molecular patterns that emerge in specific brain cell types simultaneously to the outgrowth of metastases. Dissecting the biology of these emerging patterns and their functional consequences could provide the basis to prevent metastasis but also to treat advances lesions. A key objective of ALTER-brain is the identification of newly established functional networks among previously non-connected components of the microenvironment that are critical to nurture tumour growth.
This research proposal focuses on metastasis in the brain given its rising incidence, poor therapeutic options and short survival rates upon diagnosis. ALTER-brain will use novel (i.e. spontaneous metastasis) and clinically relevant (i.e. relapse after therapy) experimental mouse models of brain metastasis combined with genetically engineered mice in which we will target specific components of the microenvironment. In addition, we will apply novel lineage tracing technologies to understand the origin and emerging heterogeneity of the reprogrammed microenvironment. Given the clinical relevance of our research, human brain metastasis provided by our clinical network will be used to validate key findings.
ALTER-brain will identify key principles underlying the unknown biology of the brain under a specific pathological pressure that might be translated to other highly prevalent disorders affecting this organ in the future.
Max ERC Funding
1 897 437 €
Duration
Start date: 2020-07-01, End date: 2025-06-30
Project acronym ANIMATE
Project Adaptive Immunity in Human Atherosclerosis: Understanding its Cellular Basis to Define Novel Immunomodulatory Therapies
Researcher (PI) Dennis Wolf
Host Institution (HI) UNIVERSITAETSKLINIKUM FREIBURG
Call Details Starting Grant (StG), LS4, ERC-2019-STG
Summary Atherosclerosis is a chronic immune disease of arteries that causes vessel-narrowing atherosclerotic plaques. Its acute complications, myocardial infarction and stroke, are the leading causes of death worldwide. Atherosclerosis is accompanied by an inflammatory and autoimmune response with CD4+ T-helper cells that recognize self-antigens, including ApoB-100 (ApoB), the main protein in low-density lipoprotein (LDL) cholesterol. Although their existence has been inferred from indirect evidence, the existence and function of atherosclerosis-specific, self-reactive CD4+ T cells on a single-cell level remains elusive. In particular, it is unclear whether these are pro- or anti-inflammatory.
Preliminary data suggest the existence of a natural pool of ApoB-reactive T-helper cells that share properties with atheroprotective T-regulatory cells but transform into pathogenic T-effector cells in the natural course of disease. This proposal aims to explore this loss of protective immunity on a cellular and function level. It employs novel tools to detect antigen-specific T cells in vivo by MHC-II multimers, mass cytometry (CyTOF), single cell RNA-sequencing (scRNA-seq), lineage-tracing mouse models, and live cell imaging. Based on the anticipated findings, this study will define a map of auto-reactive T-helper cell phenotypes in a temporal, spatial, and functional dimension. These insights will be used to identify novel immunomodulatory strategies to therapeutically stabilize the population of protective ApoB-specific T-helper cells, or to prevent their transformation into pathogenic T cell phenotypes by adoptive cells transfers, vaccination, or cytokine-blockade. In clinical association studies, a direct correlation of auto-immunity and clinical atherosclerosis will be tested.
This proposal will decipher traits of protective immunity in atherosclerosis and help to build the conceptual framework to define novel therapeutic strategies for patients.
Summary
Atherosclerosis is a chronic immune disease of arteries that causes vessel-narrowing atherosclerotic plaques. Its acute complications, myocardial infarction and stroke, are the leading causes of death worldwide. Atherosclerosis is accompanied by an inflammatory and autoimmune response with CD4+ T-helper cells that recognize self-antigens, including ApoB-100 (ApoB), the main protein in low-density lipoprotein (LDL) cholesterol. Although their existence has been inferred from indirect evidence, the existence and function of atherosclerosis-specific, self-reactive CD4+ T cells on a single-cell level remains elusive. In particular, it is unclear whether these are pro- or anti-inflammatory.
Preliminary data suggest the existence of a natural pool of ApoB-reactive T-helper cells that share properties with atheroprotective T-regulatory cells but transform into pathogenic T-effector cells in the natural course of disease. This proposal aims to explore this loss of protective immunity on a cellular and function level. It employs novel tools to detect antigen-specific T cells in vivo by MHC-II multimers, mass cytometry (CyTOF), single cell RNA-sequencing (scRNA-seq), lineage-tracing mouse models, and live cell imaging. Based on the anticipated findings, this study will define a map of auto-reactive T-helper cell phenotypes in a temporal, spatial, and functional dimension. These insights will be used to identify novel immunomodulatory strategies to therapeutically stabilize the population of protective ApoB-specific T-helper cells, or to prevent their transformation into pathogenic T cell phenotypes by adoptive cells transfers, vaccination, or cytokine-blockade. In clinical association studies, a direct correlation of auto-immunity and clinical atherosclerosis will be tested.
This proposal will decipher traits of protective immunity in atherosclerosis and help to build the conceptual framework to define novel therapeutic strategies for patients.
Max ERC Funding
1 499 946 €
Duration
Start date: 2020-01-01, End date: 2024-12-31
Project acronym Ctrl-BBB
Project Blood-brain barrier: from molecular mechanisms to intervention strategies
Researcher (PI) Benoit VANHOLLEBEKE
Host Institution (HI) UNIVERSITE LIBRE DE BRUXELLES
Call Details Consolidator Grant (CoG), LS4, ERC-2019-COG
Summary Brain endothelial cells (ECs) are endowed with a set of molecular and metabolic adaptations that stringently orchestrate the molecular and cellular transit between the brain and the circulatory system. These adaptations constitute the blood-brain barrier (BBB) and are pivotal to brain homeostasis and protection. Accordingly, BBB dysfunction is a unifying hallmark of many cerebrovascular diseases, including stroke, multiple sclerosis and neurodegeneration. Healing the BBB to treat to the brain is therefore emerging as a powerful therapeutic avenue for a spectrum of human CNS disorders. In addition, through its neuroprotective function, the BBB represents the main obstacle for CNS drug delivery. There is consequently an urgent need to identify methods to control BBB in health and disease. Of pivotal importance, BBB is not genetically hardwired, but instead results from ongoing neurovascular communications taking place between the ECs and the other components of the neurovascular unit. Shedding light on these communications, and raising our understanding to the mechanistic level will undoubtedly yield transformative therapeutic strategies for human brain disorders. A key obstacle in the study of BBB permeability resides in its complex regulation across cells and tissues. This complexity cannot be recapitulated in cell culture experiments. Our laboratory has recently identified and validated the transparent zebrafish as ideally suited to facilitate these studies, by empowering non-invasive genetic analyses of BBB function under normoxia. Together with a conserved BBB genetic instruction program, the zebrafish cerebrovasculature qualifies as a an alternative “miniature BBB model” where neurovascular communication can be studied at an unprecedented pace. Ctrl-BBB will pioneer synergistic approaches between the zebrafish and the mouse model, to bring BBB research in the era of highly parallel genetic approaches and BBB-focused therapeutic strategies for brain disorders.
Summary
Brain endothelial cells (ECs) are endowed with a set of molecular and metabolic adaptations that stringently orchestrate the molecular and cellular transit between the brain and the circulatory system. These adaptations constitute the blood-brain barrier (BBB) and are pivotal to brain homeostasis and protection. Accordingly, BBB dysfunction is a unifying hallmark of many cerebrovascular diseases, including stroke, multiple sclerosis and neurodegeneration. Healing the BBB to treat to the brain is therefore emerging as a powerful therapeutic avenue for a spectrum of human CNS disorders. In addition, through its neuroprotective function, the BBB represents the main obstacle for CNS drug delivery. There is consequently an urgent need to identify methods to control BBB in health and disease. Of pivotal importance, BBB is not genetically hardwired, but instead results from ongoing neurovascular communications taking place between the ECs and the other components of the neurovascular unit. Shedding light on these communications, and raising our understanding to the mechanistic level will undoubtedly yield transformative therapeutic strategies for human brain disorders. A key obstacle in the study of BBB permeability resides in its complex regulation across cells and tissues. This complexity cannot be recapitulated in cell culture experiments. Our laboratory has recently identified and validated the transparent zebrafish as ideally suited to facilitate these studies, by empowering non-invasive genetic analyses of BBB function under normoxia. Together with a conserved BBB genetic instruction program, the zebrafish cerebrovasculature qualifies as a an alternative “miniature BBB model” where neurovascular communication can be studied at an unprecedented pace. Ctrl-BBB will pioneer synergistic approaches between the zebrafish and the mouse model, to bring BBB research in the era of highly parallel genetic approaches and BBB-focused therapeutic strategies for brain disorders.
Max ERC Funding
2 286 543 €
Duration
Start date: 2020-10-01, End date: 2025-09-30
Project acronym EPICAMENTE
Project At the epigenetics-cancer metabolism interface
Researcher (PI) Sara Sdelci
Host Institution (HI) FUNDACIO CENTRE DE REGULACIO GENOMICA
Call Details Starting Grant (StG), LS4, ERC-2019-STG
Summary Epigenetic regulation and metabolism are of great interest in cancer research. However, physical and functional connections between these two areas remain largely unexplored. While it is commonly believed that metabolites can randomly distribute inside the cell, recent evidence rather favors the hypothesis that production of certain metabolites in specific subcellular compartments orchestrates different cellular processes. EPICAMENTE aims at exploring whether the localization of enzymatic activities on chromatin can integrate cancer metabolism with chromatin remodeling to control epigenetic regulation and tumor progression. First, I aim at providing a dataset of chromatin-bound metabolic enzymes in a comprehensive panel of cancer cell lines. By combining a chromatin fluorescent reporter cell line strategy with epigenomic approaches, I will define the epigenetic and transcriptional scenarios orchestrated by chromatin-bound metabolic enzymes, and investigate their relevance in cancer cell proliferation. Performing genetic screenings with the chromatin fluorescent reporter cell lines will allow the identification of genetic interactors mediating the epigenetic role of chromatin-bound metabolic enzymes. In parallel, I aim to screen for small molecules able to counteract the epigenetic states mediated by those metabolic enzymes. Finally, I will validate my results in in vivo cancer models, thus adding an important translational aspect to the project, and opening up new opportunities for cancer therapy. The success of this project can impact our fundamental understanding of cellular and cancer biology. In most cases, the belief is that intracellular materials reside inside steady-state membrane-based compartments, which limit the interactions between different molecular pathways. By describing the role of chromatin-bound metabolic enzymes and discovering direct connections between cancer metabolism and epigenetic regulation, I will scrutinize this belief.
Summary
Epigenetic regulation and metabolism are of great interest in cancer research. However, physical and functional connections between these two areas remain largely unexplored. While it is commonly believed that metabolites can randomly distribute inside the cell, recent evidence rather favors the hypothesis that production of certain metabolites in specific subcellular compartments orchestrates different cellular processes. EPICAMENTE aims at exploring whether the localization of enzymatic activities on chromatin can integrate cancer metabolism with chromatin remodeling to control epigenetic regulation and tumor progression. First, I aim at providing a dataset of chromatin-bound metabolic enzymes in a comprehensive panel of cancer cell lines. By combining a chromatin fluorescent reporter cell line strategy with epigenomic approaches, I will define the epigenetic and transcriptional scenarios orchestrated by chromatin-bound metabolic enzymes, and investigate their relevance in cancer cell proliferation. Performing genetic screenings with the chromatin fluorescent reporter cell lines will allow the identification of genetic interactors mediating the epigenetic role of chromatin-bound metabolic enzymes. In parallel, I aim to screen for small molecules able to counteract the epigenetic states mediated by those metabolic enzymes. Finally, I will validate my results in in vivo cancer models, thus adding an important translational aspect to the project, and opening up new opportunities for cancer therapy. The success of this project can impact our fundamental understanding of cellular and cancer biology. In most cases, the belief is that intracellular materials reside inside steady-state membrane-based compartments, which limit the interactions between different molecular pathways. By describing the role of chromatin-bound metabolic enzymes and discovering direct connections between cancer metabolism and epigenetic regulation, I will scrutinize this belief.
Max ERC Funding
1 996 904 €
Duration
Start date: 2019-11-01, End date: 2024-10-31
Project acronym EXPLOSIA
Project EXpansion and Phenotype Loss Of SMCs In Atherosclerosis: Causal effects and therapeutic possibilities
Researcher (PI) Jacob Fog Bentzon
Host Institution (HI) AARHUS UNIVERSITET
Call Details Consolidator Grant (CoG), LS4, ERC-2019-COG
Summary Atherosclerosis is considered an inflammatory disease caused by the accumulation, modification and immune cell recognition of low-density lipoproteins in the arterial wall. Plaque macrophages are held to be the main drivers of disease activity, whereas smooth muscle cells (SMCs) have traditionally been considered protective by forming fibrous tissue that stabilises plaques from undergoing rupture and causing thrombosis.
In the present project, we challenge this dichotomous view of cellular villains and heroes in atherosclerosis. Using lineage tracking techniques in mice, we and others have uncovered a large population of SMCs in plaques, which has escaped detection because the cells completely lose conventional SMC phenotype. Strikingly, we have found that the entire plaque SMC population derives from only few founder SMCs that undergo massive clonal expansion and phenotypic modulation during lesion formation. We hypothesise that the balance between the different modulated SMC subtypes and the functions they carry are central to lesion progression.
In EXPLOSIA we will address this hypothesis in 3 steps. First, we will conduct a comparative analysis of clonal structure in mice, minipigs, and humans. Second, we will determine links between SMC subtypes, their gene expression programs, and atherosclerotic disease activity by combining single-cell transcriptomics with novel techniques to alter atherosclerotic disease activity in gene-modified mice and minipigs. Third, we will develop techniques for manipulating genes in modulated plaque SMCs and test the causal role of perturbing SMC subtypes and function for lesion progression.
The aim of the project is to answer the following key questions for a deeper understanding of atherosclerosis:
- What is the clonal architecture of SMCs in human atherosclerosis?
- What is the SMC gene expression signature of atherosclerotic disease activity?
- Can interventions targeting SMCs prevent dangerous lesion development?
Summary
Atherosclerosis is considered an inflammatory disease caused by the accumulation, modification and immune cell recognition of low-density lipoproteins in the arterial wall. Plaque macrophages are held to be the main drivers of disease activity, whereas smooth muscle cells (SMCs) have traditionally been considered protective by forming fibrous tissue that stabilises plaques from undergoing rupture and causing thrombosis.
In the present project, we challenge this dichotomous view of cellular villains and heroes in atherosclerosis. Using lineage tracking techniques in mice, we and others have uncovered a large population of SMCs in plaques, which has escaped detection because the cells completely lose conventional SMC phenotype. Strikingly, we have found that the entire plaque SMC population derives from only few founder SMCs that undergo massive clonal expansion and phenotypic modulation during lesion formation. We hypothesise that the balance between the different modulated SMC subtypes and the functions they carry are central to lesion progression.
In EXPLOSIA we will address this hypothesis in 3 steps. First, we will conduct a comparative analysis of clonal structure in mice, minipigs, and humans. Second, we will determine links between SMC subtypes, their gene expression programs, and atherosclerotic disease activity by combining single-cell transcriptomics with novel techniques to alter atherosclerotic disease activity in gene-modified mice and minipigs. Third, we will develop techniques for manipulating genes in modulated plaque SMCs and test the causal role of perturbing SMC subtypes and function for lesion progression.
The aim of the project is to answer the following key questions for a deeper understanding of atherosclerosis:
- What is the clonal architecture of SMCs in human atherosclerosis?
- What is the SMC gene expression signature of atherosclerotic disease activity?
- Can interventions targeting SMCs prevent dangerous lesion development?
Max ERC Funding
1 998 875 €
Duration
Start date: 2020-08-01, End date: 2025-07-31
Project acronym GuMeCo
Project Gut-Brain Communication in Metabolic Control
Researcher (PI) Henning Fenselau
Host Institution (HI) MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Call Details Starting Grant (StG), LS4, ERC-2019-STG
Summary Communication between the gut and the brain is essential for metabolic function. Sensory afferent neurons are key gut-brain connectors that monitor gastrointestinal (GI) tract organs, including the stomach, the duodenum, the liver, and the portal vein area, and thereby critically contribute to systemic energy and glucose homeostasis regulation. Disruption of this neural gut-brain communication develops in obesity and correlates with overeating, body weight gain, and insulin resistance. However, the relevant sensory neuronal populations innervating the GI tract organs along with the pertaining underlying metabolic neurocircuitry still remain to be elucidated. To date, advances in this field have been impeded by the challenges associated with targeting distinct sensory neurons of vagal and spinal origin in a cell-type and organ-specific manner, thereby making the accurate determination of their metabolic function highly difficult. Thus, the proposed comprehensive research program will employ a combinatorial set of modern molecular systems neuroscience tools and novel mouse genetic approaches to (1) elucidate the role of specific sensory neurons in feeding behavior and glucose metabolism, (2) determine the functional metabolic neurocircuitry of GI tract-innervating vagal and spinal afferents in an organ-specific manner, (3) study the effects of obesity on their transcriptomes, and (4) map their functional connectivity as well as synaptic adaptions to downstream brain sites. Collectively, the overarching goals of these four autonomous but complementary projects are to gain greater insights into the integral components of sensory neurons as gut-brain connectors in controlling metabolism as a first step to developing new therapies to treat obesity.
Summary
Communication between the gut and the brain is essential for metabolic function. Sensory afferent neurons are key gut-brain connectors that monitor gastrointestinal (GI) tract organs, including the stomach, the duodenum, the liver, and the portal vein area, and thereby critically contribute to systemic energy and glucose homeostasis regulation. Disruption of this neural gut-brain communication develops in obesity and correlates with overeating, body weight gain, and insulin resistance. However, the relevant sensory neuronal populations innervating the GI tract organs along with the pertaining underlying metabolic neurocircuitry still remain to be elucidated. To date, advances in this field have been impeded by the challenges associated with targeting distinct sensory neurons of vagal and spinal origin in a cell-type and organ-specific manner, thereby making the accurate determination of their metabolic function highly difficult. Thus, the proposed comprehensive research program will employ a combinatorial set of modern molecular systems neuroscience tools and novel mouse genetic approaches to (1) elucidate the role of specific sensory neurons in feeding behavior and glucose metabolism, (2) determine the functional metabolic neurocircuitry of GI tract-innervating vagal and spinal afferents in an organ-specific manner, (3) study the effects of obesity on their transcriptomes, and (4) map their functional connectivity as well as synaptic adaptions to downstream brain sites. Collectively, the overarching goals of these four autonomous but complementary projects are to gain greater insights into the integral components of sensory neurons as gut-brain connectors in controlling metabolism as a first step to developing new therapies to treat obesity.
Max ERC Funding
1 500 000 €
Duration
Start date: 2020-03-01, End date: 2025-02-28
Project acronym Hemstem
Project Targeting leukaemia by modulating hematopoietic stem cell competitiveness
Researcher (PI) Claudia LENGERKE
Host Institution (HI) UNIVERSITAT BASEL
Call Details Consolidator Grant (CoG), LS4, ERC-2019-COG
Summary Human acute myeloid leukemia (AML) remains a devastating disease with less than 30% of patients surviving five years after diagnosis. Despite decades of research and detailed mo-lecular insights provided by mutational profiling, curative treatment still requires high-intensity chemotherapy and the crude approach of allogeneic stem cell transplantation – an effective, yet non-specific immunotherapy that is costly to the patient because of its severe side effects. One reason why the wealth of molecular and experimental knowledge has so far been unable to revolutionize treatments is the fact that AML is driven by small subpopulations of so-called leukemic stem cells (LSCs), which survive chemotherapy and immune surveillance. LSCs have growth advantages induced by oncogenic mutations, but are in many ways similar to healthy hematopoietic stem cells (HSCs). This similarity makes it difficult to target LSCs without simultaneously eradicating HSCs and healthy hematopoiesis derived from these cells. Like HSCs, LSCs home to protective bone marrow (BM) niches promoting stemness and therapy resistance and modify them to displace HSCs and promote their own expansion. This proposal explores strategies to target LSCs based on understanding these interactions. In Aim 1 we investigate how WNT signaling, an evolutionary conserved pathway governing stem cell self-renewal, regulates interactions between leukemic and healthy hematopoietic (stem) cells. In Aim 2, we propose to inhibit the in vivo expansion of LSCs by enhancing self-renewal and niche affinity in their natural competitors, the healthy stem cells with inborn BM homing ability. Aim 3 uses zebrafish to visualize LSC-HSC interactions and screens for molecules supporting healthy instead of (pre-) malignant hematopoiesis. Our studies will im-prove the knowledge on the complex interactions between LSCs and HSCs and provide a rationale for novel treatments that might lead to a paradigm-shift in the clinical management of AML.
Summary
Human acute myeloid leukemia (AML) remains a devastating disease with less than 30% of patients surviving five years after diagnosis. Despite decades of research and detailed mo-lecular insights provided by mutational profiling, curative treatment still requires high-intensity chemotherapy and the crude approach of allogeneic stem cell transplantation – an effective, yet non-specific immunotherapy that is costly to the patient because of its severe side effects. One reason why the wealth of molecular and experimental knowledge has so far been unable to revolutionize treatments is the fact that AML is driven by small subpopulations of so-called leukemic stem cells (LSCs), which survive chemotherapy and immune surveillance. LSCs have growth advantages induced by oncogenic mutations, but are in many ways similar to healthy hematopoietic stem cells (HSCs). This similarity makes it difficult to target LSCs without simultaneously eradicating HSCs and healthy hematopoiesis derived from these cells. Like HSCs, LSCs home to protective bone marrow (BM) niches promoting stemness and therapy resistance and modify them to displace HSCs and promote their own expansion. This proposal explores strategies to target LSCs based on understanding these interactions. In Aim 1 we investigate how WNT signaling, an evolutionary conserved pathway governing stem cell self-renewal, regulates interactions between leukemic and healthy hematopoietic (stem) cells. In Aim 2, we propose to inhibit the in vivo expansion of LSCs by enhancing self-renewal and niche affinity in their natural competitors, the healthy stem cells with inborn BM homing ability. Aim 3 uses zebrafish to visualize LSC-HSC interactions and screens for molecules supporting healthy instead of (pre-) malignant hematopoiesis. Our studies will im-prove the knowledge on the complex interactions between LSCs and HSCs and provide a rationale for novel treatments that might lead to a paradigm-shift in the clinical management of AML.
Max ERC Funding
1 984 240 €
Duration
Start date: 2020-03-01, End date: 2025-02-28
Project acronym HumanPlacenta
Project Human Placental Development and the Uterine Microenvironment
Researcher (PI) Margherita Yayoi TURCO
Host Institution (HI) THE CHANCELLOR MASTERS AND SCHOLARSOF THE UNIVERSITY OF CAMBRIDGE
Call Details Starting Grant (StG), LS4, ERC-2019-STG
Summary How does the human placenta develop and how is this influenced by the maternal uterine microenvironment? These are the central questions addressed in my proposal. Normal growth and development of the fetus depends on the placenta, the extra-embryonic organ derived from trophectoderm. Successful pregnancy depends on the earliest stages of development when placental extravillous trophoblast cells (EVT) infiltrate the uterine mucosa, the decidua. EVT invade the decidua to transform the uterine spiral arteries into a dilated vessel capable of high conductance. Deficient arterial remodelling by EVT results in miscarriage, pre-eclampsia, fetal growth restriction and stillbirth. However, excessive invasion into the uterine wall is also potentially dangerous. Thus, to achieve a successful pregnancy, a territorial boundary is drawn with a balance between fetal EVT invasion and maternal decidual cells. Understanding the molecular and cellular mechanisms underlying these maternal/fetal interactions has been challenging due both to practical and ethical limitations and lack of reliable in vitro models. I have recently derived 3D culture systems (organoids) from human decidua and placenta that will provide the essential tools. I will use these organoids combined with single cell genomics, Crispr/Cas9 genome editing and tissue engineering to study: (i) the molecular mechanisms that specify the EVT lineage (ii) the role of paracrine signalling from maternal decidual glands in regulating placental development (iii) cell-cell interactions between decidua and EVT by creating an artificial model of decidua made from tailored collagen scaffolds seeded with stromal, glandular and immune cells. My proposal capitalises on the remarkable ability of organoid cultures to faithfully model human physiology. The human uterine environment in early pregnancy is crucial for reproductive success and development of an in vitro model of placentation will have a wide-ranging impact.
Summary
How does the human placenta develop and how is this influenced by the maternal uterine microenvironment? These are the central questions addressed in my proposal. Normal growth and development of the fetus depends on the placenta, the extra-embryonic organ derived from trophectoderm. Successful pregnancy depends on the earliest stages of development when placental extravillous trophoblast cells (EVT) infiltrate the uterine mucosa, the decidua. EVT invade the decidua to transform the uterine spiral arteries into a dilated vessel capable of high conductance. Deficient arterial remodelling by EVT results in miscarriage, pre-eclampsia, fetal growth restriction and stillbirth. However, excessive invasion into the uterine wall is also potentially dangerous. Thus, to achieve a successful pregnancy, a territorial boundary is drawn with a balance between fetal EVT invasion and maternal decidual cells. Understanding the molecular and cellular mechanisms underlying these maternal/fetal interactions has been challenging due both to practical and ethical limitations and lack of reliable in vitro models. I have recently derived 3D culture systems (organoids) from human decidua and placenta that will provide the essential tools. I will use these organoids combined with single cell genomics, Crispr/Cas9 genome editing and tissue engineering to study: (i) the molecular mechanisms that specify the EVT lineage (ii) the role of paracrine signalling from maternal decidual glands in regulating placental development (iii) cell-cell interactions between decidua and EVT by creating an artificial model of decidua made from tailored collagen scaffolds seeded with stromal, glandular and immune cells. My proposal capitalises on the remarkable ability of organoid cultures to faithfully model human physiology. The human uterine environment in early pregnancy is crucial for reproductive success and development of an in vitro model of placentation will have a wide-ranging impact.
Max ERC Funding
1 992 098 €
Duration
Start date: 2020-03-01, End date: 2025-02-28
Project acronym HyperBiota
Project Exploring the diet-microbiota axis for immunomodulation and organ protection in hypertension
Researcher (PI) Nicola Wilck
Host Institution (HI) CHARITE - UNIVERSITAETSMEDIZIN BERLIN
Call Details Starting Grant (StG), LS4, ERC-2019-STG
Summary Essential hypertension damages organs such as the kidney, thereby leading to premature death. Beyond elevated blood pressure, hypertension is characterized by a pro-inflammatory immune response ahead of measurable organ damage. Activated immune cells infiltrate the kidney to cause tissue injury. However, inflammation is insufficiently addressed by today’s drugs. Current treatments do not include the gut microbiota, its metabolites and the associated lymphoid tissue – the largest immune cell reservoir in the body. We have recently shown for the first time that variations in dietary salt intake promote hypertension by modulating the immune system via the microbiota and its metabolites. Thus, the diet-microbiota axis is an important modulator of the immune response in hypertension. HyperBiota envisions a personalized, microbiome-guided immunonutrition for anti-inflammatory immunomodulation and organ protection in hypertension. It will explore the interplay between diet-dependent microbial metabolism in the intestine and the immune system in hypertension. By using an interdisciplinary approach, HyperBiota aims to 1) decipher the reciprocity of dietary composition, microbial community structure and metabolism, and immune response in hypertension. The identification of critical dietary and microbial components will enable targeted interventions. 2) Particular attention will be payed to worsening kidney function and how this affects microbial ecology and immune cell homeostasis. 3) It will investigate the extent to which the gut-associated lymphoid tissue contributes to the immune response in hypertension and its responsiveness to targeted interventions. 4) Knowledge gained in model systems will be translated and verified in mice associated with human microbial communities. Taking this approach, HyperBiota will cross borders and take a systems view on inflammation in hypertension to enable microbiome-guided immunonutrition for organ protection in hypertension.
Summary
Essential hypertension damages organs such as the kidney, thereby leading to premature death. Beyond elevated blood pressure, hypertension is characterized by a pro-inflammatory immune response ahead of measurable organ damage. Activated immune cells infiltrate the kidney to cause tissue injury. However, inflammation is insufficiently addressed by today’s drugs. Current treatments do not include the gut microbiota, its metabolites and the associated lymphoid tissue – the largest immune cell reservoir in the body. We have recently shown for the first time that variations in dietary salt intake promote hypertension by modulating the immune system via the microbiota and its metabolites. Thus, the diet-microbiota axis is an important modulator of the immune response in hypertension. HyperBiota envisions a personalized, microbiome-guided immunonutrition for anti-inflammatory immunomodulation and organ protection in hypertension. It will explore the interplay between diet-dependent microbial metabolism in the intestine and the immune system in hypertension. By using an interdisciplinary approach, HyperBiota aims to 1) decipher the reciprocity of dietary composition, microbial community structure and metabolism, and immune response in hypertension. The identification of critical dietary and microbial components will enable targeted interventions. 2) Particular attention will be payed to worsening kidney function and how this affects microbial ecology and immune cell homeostasis. 3) It will investigate the extent to which the gut-associated lymphoid tissue contributes to the immune response in hypertension and its responsiveness to targeted interventions. 4) Knowledge gained in model systems will be translated and verified in mice associated with human microbial communities. Taking this approach, HyperBiota will cross borders and take a systems view on inflammation in hypertension to enable microbiome-guided immunonutrition for organ protection in hypertension.
Max ERC Funding
1 497 250 €
Duration
Start date: 2020-02-01, End date: 2025-01-31
Project acronym InflaPML
Project Promyelocytic leukemia protein (PML) outside the tumor: a new player in the control of inflammation
Researcher (PI) Carlotta GIORGI
Host Institution (HI) UNIVERSITA DEGLI STUDI DI FERRARA
Call Details Starting Grant (StG), LS4, ERC-2019-STG
Summary Local sterile inflammation arise in many pathologic states, including several diseases of the nervous system as brain stroke, neurodegenerative diseases and epilepsy. The persistent and de-regulated inflammatory response sustains these neurological pathologies worsening their prognosis. Different molecular players, as NLRP3 and P2X7 have been shown to contribute to the progression of these illnesses triggering the release of IL-1β and recruiting cellular components of the immune response at the neurodegeneration site. Consistently, brain penetrant P2X7 antagonists are clinically used to treat epilepsy and neurodegenerative diseases, while the pharmacological modulation of IL-1β is still unsuccessful. Unfortunately, the molecular mechanism underlying neuroinflammation and NLRP3 inflammasome assembly remains elusive. Here we propose that different neuroinflammatory diseases can be linked together in a common disease pathway, of which damaged function should be targeted for therapy. Specifically we propose a new mechanism acting on IL-1β regulation: we hypothesize the existence of a new activity of PML outside tumour environment, acting at the endoplasmic reticulum-mitochondria interfaces (MAMs) as modulator of NLRP3 inflammasome. On these bases, I propose a project in which PML activity at MAMs can be the key link of different neuroinflammatory diseases. Our goals are as follow: 1) to demonstrate that PML post-transcriptionally controls NLRP3 activity at the ER/MAMs compartments and thus IL-1β release via P2X7; 2) to prove that IL-1β release have a strong influence on neuronal environment and survival, and might represent a prognostic factor; 3) to develop new drugs targeting PML/NLRP3/P2X7 axis to overcome the unexpected failure of anti-IL-1 therapies.
Summary
Local sterile inflammation arise in many pathologic states, including several diseases of the nervous system as brain stroke, neurodegenerative diseases and epilepsy. The persistent and de-regulated inflammatory response sustains these neurological pathologies worsening their prognosis. Different molecular players, as NLRP3 and P2X7 have been shown to contribute to the progression of these illnesses triggering the release of IL-1β and recruiting cellular components of the immune response at the neurodegeneration site. Consistently, brain penetrant P2X7 antagonists are clinically used to treat epilepsy and neurodegenerative diseases, while the pharmacological modulation of IL-1β is still unsuccessful. Unfortunately, the molecular mechanism underlying neuroinflammation and NLRP3 inflammasome assembly remains elusive. Here we propose that different neuroinflammatory diseases can be linked together in a common disease pathway, of which damaged function should be targeted for therapy. Specifically we propose a new mechanism acting on IL-1β regulation: we hypothesize the existence of a new activity of PML outside tumour environment, acting at the endoplasmic reticulum-mitochondria interfaces (MAMs) as modulator of NLRP3 inflammasome. On these bases, I propose a project in which PML activity at MAMs can be the key link of different neuroinflammatory diseases. Our goals are as follow: 1) to demonstrate that PML post-transcriptionally controls NLRP3 activity at the ER/MAMs compartments and thus IL-1β release via P2X7; 2) to prove that IL-1β release have a strong influence on neuronal environment and survival, and might represent a prognostic factor; 3) to develop new drugs targeting PML/NLRP3/P2X7 axis to overcome the unexpected failure of anti-IL-1 therapies.
Max ERC Funding
1 462 500 €
Duration
Start date: 2020-06-01, End date: 2025-05-31
